| AIM To explore the antidepressant effect of the total flavonoids extracted from cottonseed (CTN-T) and the possible mechanism.METHODS (1) The tail suspension test in mice, the forced swimming test in mice and rats, the learned helplessness test in rats were used to evaluate the antidepressant effect of CTN-T. (2) The serotonergic (5-HT) and noradrenergic (NE) functions in central nervous system were observed by 5-hydroxytryptophan (5-HTP) induced head twitch response test and yohimbine toxicity potentiation test in mice. Monoamine level in rats frontal cortex and hippocampus were determined after CTN-T administration by high performance liquid chromatography with electrochemical detector (HPLC-ECD). In addition, monoamine oxidase (MAO) activity in the brain of rats and mice was analyzed by fluorimetric detection. (3) Open-field test was used to observe the locomotion activity in chronic stressed rats and ELISA was used to determine the serum concentration of corticosterone with or without CTN-T administration. The expression of brain-derived neurotrophic factor (BDNF), phospho-cyclic adenosine monophosphate response element binding protein (pCREB), phospho-extracellular signal regulated kinase (pERK) in hippocampus were analyzed by western blotting.RESULTS (1) In the tail suspension test in mice, acute (160～320 mg·kg-1, ig) or repeated (60 mg·kg-1, ig, twice daily for 7 times) administration of CTN-T significantly decreased the immobility time in mice. CTN-T (40～60 mg·kg-1, ig, twice daily for 13 times) decreased the immobility time in forced swimming test in mice. In the forced swimming test in rats, CTN-T (20～60 mg·kg-1, ig, twice daily for 7 times) also decreased the immobility time. Moreover, CTN-T (100～200 mg-kg-1·d-1, ig, twice daily for 4 d) significantly decreased the number of escape failure in learned helplessness test in rats. All these effects of CTN-T were similar to imipramine (IMI), which is a classical tricyclic antidepressant. CTN-T did not influence the locomotor activity in mice at the above mentioned doses, which suggested that CTN-T has antidepressant effect. (2) CTN-T (50～75 mg·kg-1, ig, twice daily for 7 times) significantly increased 5-HTP-induced head twitches in mice. CTN-T (60～120 mg·kg-1, ig, twice daily for 7 times) slightly increased yohimbine-induced toxicity in mice, though the result did not reach statistical significance. CTN-T (25～100 mg·kg-1 ig, twice daily for 7 times) significantly increased the levels of 5-HT and NE in rats hippocampus. At the dose of 100 mg·kg-1, CTN-T significantly reduced not only the 5-HT turnover (Ratio of 5-HIAA/5-HT) in hippocampus and frontal cortex, but the level of 5-HIAA in frontal cortex as well. The activity of both MAO-A and MAO-B in brain were inhibited by either acute administration of CTN-T (450 mg·kg-1, ig) in mice or repeated administration of CTN-T (50～100 mg·kg-1, ig, twice daily for 7 times) in rats. (3) Chronic variable stressors (CVS) significantly decreased the locomotor activity in open field test and increased the serum concentration of corticosterone, while CTN-T (50～100 mg·kg-1, ig, 1 hr before each stress session) or desipramine (DMI, 10 mg·kg-1, ip, 30 min before each stress session) significantly inhibited these actions. Chronic stress induced down-regulation for the expression of BDNF, pCREB and pERK in rats hippocampus, while CTN-T (50～100 mg·kg-1, ig) or DMI (10 mg·kg-1, ip ) reversed these phenomenon significantly.CONCLUSION CTN-T has antidepressant effect in all the animal behavior models involved in this study. The mechanism might related to 1) potentiation of serotonergic and noradrenergic neurotransmission and inhibition of MAO activity in central nervous system, 2) up-regulation of BDNF signal pathways in hippocampus that further promotes neurotrophy and neural plasticity.
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